Book of Abstracts: Albany 2011

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Conversation 17
June 14-18 2011
©Adenine Press (2010)

A Critical Residue That Promotes Protein Dimerization: A Story Of Partially Exposed PHE25 IN 14-3-3σ*

Protein-protein interactions are required for biological functions and false protein-protein interactions can cause diseases such as cancer and diabetes. However, how protein recognizes each other and forms stable complexes are not fully understood. It is often difficult to differentiate a real biological relevant protein complex from the non-specific protein-protein interaction resulted from crystal packing in crystallography. Although hydrophobic interactions have been recognized as the major driving force for protein oligomerization, detailed molecular mechanism of the assembly is unknown. The simplest case of protein-protein recognition and interaction could be the association between two identical chains (homo-dimer). In this study, we employed 14-3-3σ homo-dimer as a model protein and investigated the role of hydrophobic residues at dimer interface. We found that while mutation of hydrophobic core residues does greatly compromise the dimerization activity of 14-3-3σ, mutation of half-buried-and-half-exposed interfacial residue, Phe25, surprisingly completely knocked out the activity. We found that stable homo-dimers have stable and highly packed interfacial hydrophobic cores devoid of water molecules. Phe25 plays a more important role compared with core residues by organizing both favorable hydrophobic and hydrophilic interactions for homo-dimerization. We conclude that structural stability of interfacial hydrophobic cores can be bestowed by residues outside of the core. Further investigations suggest that the organizing activity of Phe25 originates from its unique physical location, rigidity, size, and hydrophobicity. Thus, hydrophobic residues that are not deeply buried at interface may play important but different roles from the buried core residues by organizing co-operativity of core and other residues for protein oligomerization.

This work was supported in part by grant R01 CA113384 from National Institutes of Health (JTZ).


  1. Bernauer, J., Bahadur, R. P., Rodier, F., Janin, J., and Poupon, A. Bioinformatics 24, 652-658 (2008)
  2. Benzinger, A., Popowicz, G. M., Joy, J. K., Majumdar, S., Holak, T. A., and Hermeking, H. Cell Research 15, 219-227 (2005).
  3. Jones, S., and Thornton, J. M. Proc Natl Acad Sci U S A 93, 13-20 (1996)
  4. Keskin, O., Gursoy, A., Ma, B., and Nussinov, R. Chem Rev 108, 1225-1244 (2008).
  5. Keskin, O., Ma, B. Y., and Nussinov, R. Biophysical Journal 88, 5A-5A (2005).
  6. Bogan, A. A., and Thorn, K. S. Journal of Molecular Biology 280, 1-9 (1998).
  7. Zhou, Y. Q., Vitkup, D., and Karplus, M. Journal of Molecular Biology 285, 1371-1375 (1999).
  8. Lindemann, F. A. European Physical Journal Z 11, 609-612 (1910).
  9. Zhou, Y. Q., Zhou, H. Y., and Karplus, M. Journal of Molecular Biology 326, 593-606 (2003).
  10. Yang, X., Lee, W. H., Sobott, F., Papagrigoriou, E., Robinson, C. V., Grossmann, J. G., Sundstrom, M., Doyle, D. A., and Elkins, J. M. Proc Natl Acad Sci U S A 103, 17237-17242 (2006).

Jing-Yuan Liu
Zhaomin L
Huian Li
and Jian-Ting Zhang

Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202

Ph (317) 274-7645;
Fax (317) 274-7714;